title: Negative lusitropic effect of DPI 201-106 and E4031. Possible role of prolonging action potential duration.
abstract: In open-chest anesthetized dogs, the time constant of isovolumic left ventricular pressure decay increased following the intravenous administration of either E4031, a class III antiarrhythmic agent which acts by K+ channel blockade, or DPI 201-106 (DPI), a cardiotonic agent which acts by delaying Na+ channel inactivation. In addition to prolonging cardiac refractoriness, both E4031 and DPI increased left ventricular +dP/dt but without significantly altering -dP/dt. Consequently, the value of the ratio (+dP/dt)/(-dP/dt) increased. There were no significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. Since both E4031 and DPI prolonged the action potential duration (APD) and the refractory period, and slowed relaxation in vivo, the possibility of a causal link between these effects was further investigated under in vitro conditions. In isometrically contracting rabbit papillary muscles, E4031 and DPI increased peak developed tension (DT) and its maximal rate of rise (+T). Since the maximal rate of fall of DT (-T) did not increase by the same factor that +T increased, the value of the ratio +T/-T increased. Time to half relaxation increased, whereas time to peak tension was not significantly changed by either E4031 or DPI. These negative lusitropic effects produced by E4031 or DPI were not observed when equivalent increases in contractility were produced by increasing the extracellular Ca2+ concentration. The effective refractory period measured in the papillary muscles increased following superfusion with either of the two drugs, consistent with their known ability to increase APD. A causal link between the prolongation of APD and the negative lusitropic effects of E4031 and DPI is postulated as the possible mechanism.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, West Point, PA.
authors.forename: H E
authors.initials: HE
authors.lastname: Cingolani
authors.forename: R T
authors.initials: RT
authors.lastname: Wiedmann
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: H C
authors.initials: HC
authors.lastname: Wenger
authors.forename: A L
authors.initials: AL
authors.lastname: Scott
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
authors.forename: R B
authors.initials: RB
authors.lastname: Stein
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; C046261:DPI 201-106; D002118:Calcium